DESCRIPTION: The overall goal of this project is to determine the role of loss of DNA mismatch repair (IVIMR) in the development of cellular drug resistance in vitro and in vivo. This project focuses on the new discovery that loss of IVIIVIR causes the cells to become resistant to cisplatin and carboplatin. The Specific Aims are directed at the following questions: 1) does treatment with cisplatin enrich for pre-existing MMR-deficient cells in a tumor population growing in vivo?; 2) does treatment with cisplatin enrich for MMR-deficient cells in patients?; 3) does loss of MMR increase the spontaneous rate of mutation to resistance to other clinically important chemotherapeutic agents?; and 4) does loss of MMR increase the ability of cisplatin to mutagenize tumor cells to other chemotherapeutic agents?